Hepatocellular carcinoma (HCC) is one of the most common and lethal cancer types worldwide. Recent studies found Coiled-coil domain-containing protein 50 (CCDC50) could regulate the nuclear factor kappa-B and p53 signalling pathways in cancer. Nevertheless, the underlying biological function and potential mechanisms of CCDC50 driving the progression of HCC remain unclear. In this study, we found that CCDC50 was up-regulated in HCC, and its higher expression was associated with adverse clinical outcomes and poor clinical characteristics. The results of the Cox regression analysis revealed that CCDC50 was an independent factor for the prognosis of HCC. Meanwhile, we also established a nomogram based on CCDC50 to predict the 1-, 3-, or 5-year survival in HCC patients. Furthermore, we found that DNA hypomethylation results in its overexpression in HCC. In addition, functional annotation confirmed that CCDC50 was mainly involved in the neuroactive ligand-receptor interaction and protein digestion and absorption. Importantly, we found that CCDC50 was highly expressed in HCC cell lines. Depletion of CCDC50 significantly inhibits HCC cell proliferation and migration abilities. This is the first study to identify CCDC50 as a new potential prognostic biomarker and characterize the functional roles of CCDC50 in the progression of HCC, and provides a novel potential diagnostic and therapeutic biomarker for HCC in the future.